Tyrosol and Olive Oil Ameliorate Sodium Arsenate‑Induced Nephrotoxicity by Modulating of Oxidative Stress and Histological Changes in Mice

Mehryar Zargari, Mona Mohammadian, Abbasali K. Malekshah, Manijeh Mianabadi, Amir E. Mogaddam, Fereshteh T. Amiri


Background: Sodium arsenate (Na 3As0 4, Sodium As) is an important toxic substance that leads to nephrotoxicity. Due to having bioactive molecules, such as polyphenols and tyrosol, olive oil plays a significant role in scavenging free radicals. This study aimed to investigate the effects of olive oil and tyrosol on As‑induced nephrotoxicity. Methods: In our study, 42 adult male BALB/c mice were randomly divided into six groups: control (normal saline), olive oil (0.4 ml/d, gavage), tyrosol (5 mg/kg/d), Sodium As (15 mg/kg), olive oil + Sodium As, and tyrosol + Sodium As (olive oil and tyrosol received one hour before Sodium As). Drugs were administreted once daily for 30 consecutive days. On the 31st day of the study, oxidative stress parameters in kidney tissue, FRAP in plasma, renal function parameters in serum, and histopathological assays were performed. Results: Sodium As‑induced renal damage as characterized by a significant increase of creatinine and BUN (P < 0.001) and histopathological changes. Also, Sodium As markedly altered oxidative stress biomarkers such as a significant increase in MDA (P < 0.001) and significantly decreased in FRAP and GSH (P < 0.01). Olive oil and tyrosol administration significantly improved the renal antioxidant defense system and decreased MDA concentration, markedly preserving the tissue structure and functional markers of kidney. However, these effects were more effective for tyrosol than olive oil. Conclusions: Our results suggest that olive oil and tyrosol can be used as a protective agent in preventing Sodium As‑induced nephrotoxicity due to antioxidant property.


4‑hydroxyphenylethanol; acute kidney injury; histology; olive oil; oxidative stress; sodium arsenate

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Nuntharatanapong N, Chen K, Sinhaseni P, Keaney JF. EGF

receptor‑dependent JNK activation is involved in arsenite‑induced

p21Cip1/Waf1 upregulation and endothelial apoptosis. Am J

Physiol Heart Circ Physiol 2005;58:H99‑107.

Andrew AS, Jewell DA, Mason RA, Whitfield ML, Moore JH,

Karagas MR. Drinking‑water arsenic exposure modulates

gene expression in human lymphocytes from a US population.

Environ Health Perspect 2008;116:524‑31.

Rahman A, Vahter M, Ekström E‑C, Persson L‑Å. Arsenic

exposure in pregnancy increases the risk of lower respiratory

tract infection and diarrhea during infancy in Bangladesh.

Environ Health Perspect 2011;119:719‑24.

Smith AH, Marshall G, Yuan Y, Ferreccio C, Liaw J,

von Ehrenstein O, et al. Increased mortality from lung cancer

and bronchiectasis in young adults after exposure to arsenic

in utero and in early childhood. Environ Health Perspect


Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F,

et al. Arsenic exposure from drinking water, and all‑cause

and chronic‑disease mortalities in Bangladesh (HEALS):

A prospective cohort study. Lancet 2010;376:252‑8.

Singh MK, Yadav SS, Yadav RS, Chauhan A, Katiyar D,

Khattri S. Protective effect of Emblica‑officinalis in arsenic

induced biochemical alteration and inflammation in mice.

SpringerPlus 2015;4:438.

Patra PH, Bandyopadhyay S, Kumar R, Datta BK, Maji C,

Biswas S, et al. Quantitative imaging of arsenic and its species

in goat following long term oral exposure. Food Chem Toxicol


Thomas DJ. Molecular processes in cellular arsenic metabolism.

Toxicol Appl Pharmacol 2007;222:365‑73.

Rani VU, Sudhakar M, Ramesh A. Protective effect of Pueraria

tuberosa Linn. in arsenic induced nephrotoxicity in rats. Asian J

Pharm Res 2017;7:15‑20.

Ghabaee Z, Nasiry D, Amiri FT, Moghaddam AE,

Khalatbary AR, Zargari M. Administration of zinc against

arsenic‑induced nephrotoxicity during gestation and lactation in

rat model. J Nephropathol 2017;6:74‑80.

Prabu SM, Muthumani M. Silibinin ameliorates arsenic induced

nephrotoxicity by abrogation of oxidative stress, inflammation

and apoptosis in rats. Mol Biol Rep 2012;39:11201‑16.

Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ,

Willett WC. Trans fatty acids and cardiovascular disease. N Engl

J Med 2006;354:1601‑13.

Gill CI, Boyd A, McDermott E, McCann M, Servili M,

Selvaggini R, et al. Potential anti‑cancer effects of virgin olive

oil phenolson colorectal carcinogenesis models in vitro. Int J

Cancer 2005;117:1‑7.

Cicerale S, Lucas L, Keast R. Antimicrobial, antioxidant and

anti‑inflammatory phenolic activities in extra virgin olive oil.

Curr Opin Biotechnol 2012;23:129‑35.

Ghorbel I, Elwej A, Fendri N, Mnif H, Jamoussi K, Boudawara T,

et al. Olive oil abrogates acrylamide induced nephrotoxicity by

modulating biochemical and histological changes in rats. Ren

Fail 2017;39:236‑45.

Ahmadvand H, Ghabaee DNZ, Malekshah AK, Navazesh A.

Virgin olive oil ameliorates deltamethrin‑induced nephrotoxicity

in mice: A biochemical and immunohistochemical assessment.

Toxicol Rep 2016;3:584‑90.

Loru D, Incani A, Deiana M, Corona G, Atzeri A, Melis M, et al.

Protective effect of hydroxytyrosol and tyrosol against oxidative

stress in kidney cells. Toxicol Indus Health 2009;25:301‑10.

Deiana M, Corona G, Incani A, Loru D, Rosa A, Atzeri A, et al.

Protective effect of simple phenols from extravirgin olive oil

against lipid peroxidation in intestinal Caco‑2 cells. Food Chem

Toxicol 2010;48:3008‑16.

Bu Y, Rho S, Kim J, Kim MY, Lee DH, Kim SY, et al.

Neuroprotective effect of tyrosol on transient focal cerebral

ischemia in rats. Neurosci Lett 2007;414:218‑21.

Lee KM, Hur J, Lee Y, Yoon B‑R, Choi SY. Protective effects of

tyrosol against oxidative damage in L6 muscle cells. Food Sci

Technol Res 2018;24:943‑7.

Salucci S, Burattini S, Battistelli M, Buontempo F, Canonico B,

Martelli AM, et al. Tyrosol prevents apoptosis in irradiated

keratinocytes. J Dermatol Sci 2015;80:61‑8.

Mohammadian M, Mianabadi M, Zargari M, Karimpour A,

Khalafi M, Amiri FT. Effects of olive oil supplementation on

sodium arsenate‑induced hepatotoxicity in mice. Int J Prev Med


Yu N‑H, Pei H, Huang Y‑P, Li Y‑F. (‑)‑Epigallocatechin‑3‑Gallate

inhibits arsenic‑induced inflammation and apoptosis through

suppression of oxidative stress in mice. Cell Physiol Biochem


Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP)

as a measure of “antioxidant power”: The FRAP assay. Anal

Biochem 1996;239:70‑6.

Ghabaee DNZ, Amiri FT, Moghaddam AE, Khalatbary AR,

Zargari M. Administration of zinc against arsenic‑induced

nephrotoxicity during gestation and lactation in rat model.

J Nephropathol 2017;6:74‑80.

Robles‑Osorio ML, Sabath‑Silva E, Sabath E. Arsenic‑mediated

nephrotoxicity. Renal Fail 2015;37:542‑7.

Gong X, Ivanov VN, Davidson MM, Hei TK.

Tetramethylpyrazine (TMP) protects against sodium

arsenite‑induced nephrotoxicity by suppressing ROS production,

mitochondrial dysfunction, pro‑inflammatory signaling pathways

and programed cell death. Arch Toxicol 2015;89:1057‑70.

Rizwan S, Naqshbandi A, Farooqui Z, Khan AA, Khan F.

Protective effect of dietary flaxseed oil on arsenic‑induced

nephrotoxicity and oxidative damage in rat kidney. Food Chem

Toxicol 2014;68:99‑107.

Kadiiska M, Gladen B, Baird D, Germolec D, Graham L,

Parker C, et al. Biomarkers of oxidative stress study II: Are

oxidation products of lipids, proteins, and DNA markers of CCl4

poisoning? Free Radic Biol Med 2005;38:698‑710.

Zang H, Shen P, Xu Q, Zhang L, Xia G, Sun J, et al. Synthesis

and biological activities of tyrosol phenolic acid ester derivatives.

Chem Nat Compd 2019;55:1043‑9.

Ghorbel I, Elwej A, Jamoussi K, Boudawara T, Kamoun NG,

Zeghal N. Potential protective effects of extra virgin olive oil

on the hepatotoxicity induced by co‑exposure of adult rats to

acrylamide and aluminum. Food Funct 2015;6:1126‑35.

Ghorbel I, Khemakhem M, Boudawara O, Marrekchi R,

Jamoussi K, Amar RB, et al. Effects of dietary extra virgin olive

oil and its fractions on antioxidant status and DNA damage in

the heart of rats co‑exposed to aluminum and acrylamide. Food

Funct 2015;6:3098‑108.

Paiva‑Martins F, Gordon MH, Gameiro P. Activity and location

of olive oil phenolic antioxidants in liposomes. Chem Phys

Lipids 2003;124:23‑36.

Rosillo MÁ, Alcaraz MJ, Sánchez‑Hidalgo M,

Fernández‑Bolaños JG, Alarcón‑de‑la‑Lastra C, Ferrándiz ML.

Anti‑inflammatory and joint protective effects of extra‑virgin

olive‑oil polyphenol extract in experimental arthritis. J Nutr

Biochem 2014;25:1275‑81.

Erol‑Dayi Ö, Arda N, Erdem G. Protective effects of olive

oil phenolics and gallic acid on hydrogen peroxide‑induced

apoptosis. Eur J Nutr 2012;51:955‑60.

Tavafi M, Ahmadvand H, Toolabi P. Inhibitory effect of olive

leaf extract on gentamicin‑induced nephrotoxicity in rats. Iran J

Kidney Dis 2012;6:25‑32.

Al‑Attar AM, Alrobai AA, Almalki DA. Protective effect of

olive and juniper leaves extracts on nephrotoxicity induced by

thioacetamide in male mice. Saudi J Biol Sci 2017;24:15‑22.

Silva S, Sepodes B, Rocha J, Direito R, Fernandes A, Brites D,

et al. Protective effects of hydroxytyrosol‑supplemented refined

olive oil in animal models of acute inflammation and rheumatoid

arthritis. J Nutr Biochem 2015;26:360‑8.

Pereira‑Caro G, Mateos R, Sarria B, Cert R, Goya L, Bravo L.

Hydroxytyrosyl acetate contributes to the protective effects

against oxidative stress of virgin olive oil. Food Chem


Bulotta S, Celano M, Lepore SM, Montalcini T, Pujia A, Russo D.

Beneficial effects of the olive oil phenolic components oleuropein

and hydroxytyrosol: Focus on protection against cardiovascular

and metabolic diseases. J Transl Med 2014;12:219.

Cicerale S, Lucas L, Keast R. Biological activities of phenolic

compounds present in virgin olive oil. Int J Mol Sci 2010;11:458‑79.

Soni M, Prakash C, Dabur R, Kumar V. Protective effect of

hydroxytyrosol against oxidative stress mediated by arsenicinduced neurotoxicity in rats. Applied biochemistry and

biotechnology, 2018;186:27-39.

Kalaiselvan I, Dicson SM, Kasi PD. Olive oil and its phenolic

constituent tyrosol attenuates dioxin‑induced toxicity in

peripheral blood mononuclear cells via an antioxidant‑dependent

mechanism. Nat Prod Res 2015;29:2129‑32.

Miro‑Casas E, Covas M, Fito M, Farre‑Albadalejo M,

Marrugat J, De La Torre R. Tyrosol and hydroxytyrosol are

absorbed from moderate and sustained doses of virgin olive oil

in humans. Eur J Clin Nutr 2003;57:186‑90.

Dewapriya P, Himaya S, Li Y‑X, Kim S‑K. Tyrosol exerts a

protective effect against dopaminergic neuronal cell death in in vitro

model of Parkinson’s disease. Food Chem 2013;141:1147‑57.

Stiuso P, Bagarolo ML, Ilisso CP, Vanacore D, Martino E,

Caraglia M, et al. Protective effect of tyrosol and

S‑adenosylmethionine against ethanol‑induced oxidative stress of

Hepg2 cells involves sirtuin 1, P53 and Erk1/2 signaling. Int J

Mol Sci 2016;17:622.

Gowda S, Desai PB, Kulkarni SS, Hull VV, Math AA,

Vernekar SN. Markers of renal function tests. N Am J Med Sci


Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI,

Greene T, et al. Estimating glomerular filtration rate from serum

creatinine and cystatin C. N Engl J Med 2012;367:20‑9.

Yu M, Xue J, Li Y, Zhang W, Ma D, Liu L, et al. Resveratrol

protects against arsenic trioxide‑induced nephrotoxicity by

facilitating arsenic metabolism and decreasing oxidative stress.

Arch Toxicol 2013;87:1025‑35.